Marilen Benner

CHAPTER 1 16 CONSIDERING DIFFERENT ANGLES Not only maternal immune cells of the decidua have specialized regulatory functions. Previous studies suggest a number of different angles from which to investigate the balance between maternal and fetal cells: 1) Trophoblasts possess mechanisms to facilitate immune evasion. EVT express immune-modulatory receptors, which match ligands of dNK cells (HLA-G – LILRB1), macrophages (IL10R – IL10) , and T cells (PDL1- PD1) (48). Functionally, this for example translates to the ability of EVT to inhibit proliferation of T cells, and to induce differentiation of CD4+ T cells towards Treg cell in vitro (38, 49). Trophoblasts secrete cytokines that strongly impact the local immune environment. Examples are IL-34, which polarizes decidual macrophages towards a tolerogenic phenotype, and IL-35, which converts naïve T cells to IL-35-producing regulatory T cells and, in mice, thereby prohibiting pregnancy loss (49, 50). 2) Cells of the uterine tissue influence the local immune environment. Like trophoblast cells, cells of the uterus are equipped with surface molecules to facilitate tolerogenic ligand-receptor interactions with decidual immune cells (48). Through their secretion of indoleamine 2,3-dioxygenase (IDO) and prostaglandin E (PGE), decidual stromal cells (DSC) were shown to reduce NK cell proliferation and cytolytic activity, and inhibit dendritic cell (DC) differentiation (51). Additionally, DSC hamper local T cell accumulation through their reduced expression of Th1 cell - attracting chemokines as a result of epigenetic silencing (52). 3) External factors contribute to a tolerance-favoring milieu (e.g. seminal fluid, microbiota). Adding to the complexity, there are even more contributors to consider than maternal and fetal cells. Seminal fluid was shown to regulate inflammatory gene expression in cervical and vaginal epithelial cells (53, 54). It contains soluble factors, such as transforming growth factor- β (TGF- β ) and PGE, with the ability to modify the induction of Treg (55). Even though direct experimental evidence of uterine contribution of this immune-modulatory action is yet to be exposed, a contribution of seminal fluid to successful implantation is likely; contact with seminal fluid during the course of ART increased clinical pregnancy rates (56). Another external contributor able to enter the uterus, and modify immunity, are microbiota; a topic of heavy debate as the uterus was previously regarded sterile. The discussion on the contribution of bacteria to pregnancy success lifted up with the discovery of commensal colonization of the placenta, and with 16S rRNA sequencing techniques becoming more accessible, studies on endometrial and placental microbiota are rising (57-60).